The complement system is a critical component of the innate immune response that all animal viruses encounter during natural infections. While it is clear that complement (C') is an important factor in neutralization of many RNA viruses, very few mechanistic details are known about how C' regulates paramyxovirus infections and pathology in the respiratory tract. Here, we seek to fill gaps in understanding of interactions of complement (C') with the paramyxoviruses Simian Virus 5 (SV5), Mumps virus (MuV) and Respiratory Syncytial Virus (RSV). This project emerged from recent findings that: 1) C' plays an essential role in neutralization of both SV5 and MuV, 2) SV5 and RSV induce expression of cellular Regulators of Complement Activation (RCA) and some RCAs are incorporated into SV5, MuV and RSV virions, and 3) SV5 growth is enhanced in lungs of C'-depleted mice, but growth in the nasal tissue is not affected. Our long term goal is to understand the cellular and viral factors that dictate the outcome of interactions of paramyxoviruses with C' in the respiratory tract of infected animals. Aim 1 will determine the mechanism of incorporation of RCAs into SV5, MuV and RSV virions and the role of virion-associated RCAs in neutralization and pathology in vivo. This will involve the use of an innovative EM approach, VLPs, and novel viruses that overexpress RCAs. Work in Aim 2 will define the mechanisms by which SV5, MuV and RSV differentially upregulate RCA expression and how infected cells are spared from lysis. Our results show that SV5 growth is enhanced in the lung but not the nasal tissue of C'-depleted mice. In Aim 3 we will use genetically deficient mice to distinguish between a direct role for C' in SV5 and RSV neutralization versus a role for C' in differential recruitment of immune cells to tissues. New concepts that have emerged from our work address the questions of: 1) how individual RCAs contribute to viral clearance and pathogenesis in the respiratory tract, 2) what signals direct RCA incorporation into budding particles, 3) what signaling pathways are exploited by paramyxoviruses to make cells resistant to C'-mediated lysis, and 4) what mechanisms dictate differential roles for C' in limiting viral load in the lung but not in the nasal tissue of infected animals. Addressing these concepts will have a significant impact on our understanding of this understudied area of innate immunity to viruses.